| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
After 24 weeks: (1) To assess the effect of co-administration of MK-0431 and metformin compared with the effect of metformin monotherapy on HbA1c; (2) To assess the effect of co-administration of MK-0431 and metformin compared with the effect of MK-0431 monotherapy on HbA1c; (3) To assess the safety and tolerability of co-administration of MK-0431 and metformin, MK-0431 monotherapy, and metformin monotherapy, including the incidence of selected gastrointestinal adverse events (i.e., abdominal pain, nausea, vomiting, and diarrhea).
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| E.2.2 | Secondary objectives of the trial |
| See Protocol-036 for the secondary objectives. |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients who meet the criteria listed below will be recruited for enrollment into the study. All laboratory measurements are to be performed after an overnight fast ≥12 hours in duration.
a. Patient has type 2 diabetes mellitus (T2DM).
b. Patient is ≥18 and ≤78 years of age.
c. Patient has an understanding of the study procedures and agrees to participate in the study by giving written informed consent.
d. Patient is not pregnant or breast-feeding and does not plan to become pregnant for the duration of the study and poststudy follow-up period.
e. Patient is a male, or a female who is highly unlikely to conceive, as indicated by at least one “yes” answer to the following questions:
1) Patient is a male.
2) Patient is a surgically sterilized female.
3) Patient is a postmenopausal female ≥45 years of age with >2 years since last menses.
4) Patient is a non-sterilized premenopausal female and agrees to: (1) use 2 adequate methods of contraception to prevent pregnancy (either 2 barrier methods or a barrier method plus a hormonal contraceptive method) or (2) abstain from heterosexual activity throughout the study starting with Visit 1 and for 14 days after the last dose of study medication. Refer to Section I.E.12.a. for description of acceptable methods of contraception.
f. Patient meets one of the following criteria as indicated by a “yes” answer to one of the following:
1) Patient is currently not on an antihyperglycemic agent (off therapy for ≥8 weeks) and has a Visit 1/Screening Visit HbA1c ≥7.5% and ≤11%.
OR
Patient is in 1 of the following 3 categories AND based upon review of the patient’s current diet, medical regimen, and Visit 1/Screening Visit HbA1c, patient is considered by the investigator to be likely to meet Visit 3 inclusion criterion of HbA1c ≥7.5% to ≤11% with diet/exercise counseling:
2) Patient is currently not on an antihyperglycemic agent (off therapy for ≥8 weeks) and has a Visit 1/Screening Visit HbA1c >11%.
3) Patient is currently on antihyperglycemic agent monotherapy or dual oral combination therapy and has a Visit 1/Screening Visit HbA1c ≥7% and ≤10%.
4) Patient is currently on dual oral combination therapy (which contains at least one agent dosed at >50% maximal labeled dose), has Visit 1/Screening Visit HbA1c ≥6.5% and <7%, and has been approved by the Merck clinical monitor.
NOTE: Patients currently not on an antihyperglycemic agent, but off therapy for <8 weeks, may be enrolled following discussion with and approval by the Merck Clinical Monitor.
g. HbA1c ≥7.5% and ≤11% measured at Visit 3. NOTE: Once a patient has initiated placebo run-in at Visit 3, if the Visit 3 HbA1c is not within the Visit 3 HbA1c inclusion criterion, a single repeat measurement may be performed at the discretion of the investigator. If repeat value meets Visit 3 HbA1c inclusion criterion, patient may continue in study.
h. Patient has ≥75% compliance (as measured by tablet count) with placebo treatment during run-in.
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| E.4 | Principal exclusion criteria |
see the protocol for comprehensive list and additional clarification.
a. Patient has a history of type 1 diabetes or ketoacidosis.
b. Patient required insulin within the prior 8 weeks.
c. Patient has an hypersensitivity contraindication to biguanide medication.
d. Patient has a serum ALT or AST >2.0-fold the Upper Limit of Normal. Note: Patients whose serum ALT or AST exceeds this limit may be retested one time if the investigator does not believe the value reflects the patient’s clinical status.
e. Serum creatinine 123.8 µmol/L in men and 114.9 µmol/L in women or estimated creatinine clearance (using Cockcroft-Gault formula) <60 mL/min.
f. Patient has cirrhosis or active liver disease or active nephropathy or chronic progressive neuromuscular disorder or any other condition or therapy which, in the opinion of the investigator or Merck medical monitor, might pose a risk to the patient or make participation not in the patient’s best interest.
g. Patient has new or worsening signs or symptoms of coronary heart disease within the past 3 months or has any of the following disorders within the past 6 months: 1) Acute coronary syndrome. 2). Coronary artery intervention. 3) Stroke or transient ischemic neurological disorder. 4) Congestive heart failure treated with pharmacologic therapy. h. Patient is HIV positive.
i. Patient has a clinically important hematological disorder.
j. Patient has a history of malignancy. Exceptions: 1) patients with adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix may participate; 2) patients with other malignancies which have been successfully treated ≥5 years prior to screening, where in the judgment of both the investigator and treating physician, appropriate follow-up has revealed no evidence of recurrence from the time of treatment through the time of screening; and 3) patients who, in the joint opinion of homa, malthe Merck medical monitor and investigator, are highly unlikely to sustain a recurrence during the duration of the study. However, patients with a history of leukemia, lympignant melanoma, myeloproliferative disease, or renal cell carcinoma are ineligible for the study regardless of the time since treatment, and in such cases, no exceptions will apply.
k. Patient has a history of alcohol or drug abuse within the past year 3 years.
l. Patient has a fasting plasma glucose consistently >270 mg/dL (14.99 mmol/L) and is not considered likely to improve glycemic control with diet and exercise counseling.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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